Hemophagocytic Lymphohistiocytosis (HLH) or Macrophage Activation Syndrome (MAS)? A Lethal Case of Malignancy-Associated Hemophagocytic Lymphohistiocytosis in a Patient With Concurrent Autoimmune Disease

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by uncontrolled macrophage and T-cell activation leading to multiorgan failure. While primary HLH has a genetic basis, secondary HLH can arise from various triggers. Macrophage activation syndrome (MAS) is a subtype of HLH associated with autoimmune disorders, whereas malignancy-associated HLH (mHLH) is typically linked to cancers, particularly T-cell lymphomas. HLH is frequently underrecognized and may initially be mistaken for MAS due to overlapping clinical and laboratory findings, especially in the context of an occult malignancy. We present a 58-year-old male who presented with fever, cytopenias, and transaminitis and met six of the HLH-2004 diagnostic criteria. MAS was the initial working diagnosis; however, a bone marrow biopsy demonstrated hemophagocytosis and T-cell lymphoma, confirming mHLH. Despite targeted treatment, the patient experienced progressive multiorgan failure and was transitioned to hospice care. This case highlights the diagnostic complexity of HLH and the importance of distinguishing mHLH from MAS. Because therapeutic strategies differ based on the predominant trigger, autoimmune versus malignant, early recognition and accurate classification are essential to optimize outcomes and avoid delays in appropriate therapy.